SARM1

spinqualitylabelsall models Human SARM1 complex with NAD(+) (PDB ID 7cm6). Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Function SARM1 or NAD(+) hydrolase or sterile alpha and TIR motif-containing protein 1 or NADase is a NAD-cleaving enzyme whose activation triggers Wallerian axon destruction after injury. SARM1 is thought to be a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+ and inducing axonal demise. SARM1-induced axon destruction can be counteracted by increased NAD+ synthesis. Disease SARM1 mutations were found in ALS patients. SARM1 induces axonal degeneration after nerve injury and in other neuropathological conditions, such as chemotherapy induced peripheral neuropathy (CIPN), a dose-restricting chemotherapy side effect,. Consistent with its pro-degenerative function, genetic ablation of SARM1 protects against axonal and other types of neuronal degeneration, without inflicting any apparent impediments on the animal models. Particularly, it was demonstrated that SARM1 ablation provides protection against CIPN induced by the widely used chemotherapy agents vincristine, cisplatin and paclitaxel. Structural highlights The 3D structure of SARM1 shows the octamer structure with outer ring dimension of 200A, inner ring of 45A and thickness of 60A. The 3 domains of SARM1 are ARM, SAM and TIR. The interaction of the ARM and TIR domains cause the autoinhibition of SARM1. NAD(+) binding pocket is at the concave side of the ARM domain. NAD(+)/protein interactions. The domain topology includes an N-terminal ARM domain, followed by two SAM and one TIR domain. NADase activity requires homo-oligomerization of TIR domains, which is naturally facilitated by the SAM domains through complementing electrostatic and hydrophobic interactions that assembles eight protomers into a closed ring structure,. The ARM domain inhibits NADase activity in cultured cells and in axons. In the auto-inhibitory conformation, a tightly packed arrangement of overlapping ARM domains surrounds the SAM core ring and supports TIR docking in a way that keeps them separated from each other to prevent their oligomerization and NADase activity. Accordingly, SARM1 activation involves a conformational re-arrangement that would allow nearing of the TIR domains, as demonstrated by the introduction of NMN or by gain-of-function point mutations that disturb ARM-TIR interactions,,,. 3D structures of SARM1 SARM1 3D structures

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Michal Harel, Alexander Berchansky